Skip to main content

Advertisement

SpringerLink
Log in

Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD.

Methods

We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399).

Results

The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3–4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis.

Conclusions

In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.

    Article  PubMed  Google Scholar 

  2. Watanabe S, Hashimoto E, Ikejima K, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol. 2015;50(4):364–77.

    Article  PubMed  Google Scholar 

  3. Tateishi R, Okanoue T, Fujiwara N, et al. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol. 2015;50(3):350–60.

    Article  CAS  PubMed  Google Scholar 

  4. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–97.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Seko Y, Sumida Y, Tanaka S, et al. Predictors of malignancies and overall mortality in Japanese patients with biopsy-proven non-alcoholic fatty liver disease. Hepatol Res. 2015;45(7):728–38.

    Article  CAS  PubMed  Google Scholar 

  6. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917–23.

    Article  PubMed  Google Scholar 

  7. Hossain NI, Afendy A, Stepanova M. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(11):1224–9.

    Article  CAS  PubMed  Google Scholar 

  8. Liou I, Kowdley KV. Natural history of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006;40(Suppl 1):S11–6.

    PubMed  Google Scholar 

  9. Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin N Am. 2007;91(6):1125–49.

    Article  CAS  PubMed  Google Scholar 

  10. Nakahara T, Hyogo H, Yoneda M, et al. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. 2014;49(11):1477–84.

    Article  CAS  PubMed  Google Scholar 

  11. Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. Gastroenterol Hepatol. 2012;35:32–41.

    Article  PubMed  Google Scholar 

  12. Chalasani N, Guo X, Loomba R, et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology. 2010;139:1567–76 (1576.e1–6).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7:e1001324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kawaguchi T, Sumida Y, Umemura A, et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One. 2012;7:e38322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yuan X, Waterworth D, Perry JRB, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008;83:520–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53:1883–94.

    Article  CAS  PubMed  Google Scholar 

  17. Guyot E, Sutton A, Rufat P, et al. PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction inpatients with cirrhosis. J Hepatol. 2013;58:312–8.

    Article  CAS  PubMed  Google Scholar 

  18. Nischalke HD, Berger C, Luda C, et al. The PNPLA3 rs738409 148 M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis. PLoS One. 2011;6:e27087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Trepo E, Guyot E, Ganne-Carrie N, et al. PNPLA3 (rs738409 C > G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatology. 2012;55:1307–8.

    Article  CAS  PubMed  Google Scholar 

  20. Trepo E, Nahon P, Bontempi G, et al. Association between the PNPLA3 (rs738409 C > G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology. 2014;59(6):2170–7.

    Article  CAS  PubMed  Google Scholar 

  21. Valenti L, Rumi M, Galmozzi E, et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology. 2011;53:791–9.

    Article  CAS  PubMed  Google Scholar 

  22. Falleti E, Fabris C, Cmet S, et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int. 2011;31:1137–43.

    Article  CAS  PubMed  Google Scholar 

  23. Liu YL, Patman GL, Leathart JB, et al. Carriage of the PNPLA3 rs738409 C < G polymorphism confers an increased risk of nonalcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61:75–81.

    Article  CAS  PubMed  Google Scholar 

  24. Ueyama M, Nishida N, Korenaga M, et al. The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol. 2016;51(4):370–9.

    Article  CAS  PubMed  Google Scholar 

  25. Takeuchi Y, Ikeda F, Moritou Y, et al. The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis. J Gastroenterol. 2013;48(3):405–12.

    Article  CAS  PubMed  Google Scholar 

  26. Seko Y, Sumida Y, Tanaka S, et al. Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression. Hepatol Res. 2016. doi:10.1111/hepr.12840.

  27. Hyysalo J, Gopalacharyulu P, Bian H, et al. Circulating triacylglycerol signatures in nonalcoholic fatty liver disease associated with the I148M variant in PNPLA3 and with obesity. Diabetes. 2014;63:312–22.

    Article  CAS  PubMed  Google Scholar 

  28. Ruhanen H, Perttilä J, Hölttä-Vuori M, et al. PNPLA3 mediates hepatocyte triacylglycerol remodeling. J Lipid Res. 2014;55:739–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pirazzi C, Adiels M, Burza MA, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148 M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012;57:1276–82.

    Article  CAS  PubMed  Google Scholar 

  30. Pirazzi C, Valenti L, Motta BM, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23:4077–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Valenti L, Al-Serri A, Daly AK, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(4):1209–17.

    Article  CAS  PubMed  Google Scholar 

  32. Matsuura K, Sawai H, Ikeo K, et al. Japanese genome-wide association study group for viral hepatitis. genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology. 2017;152(6):1383–94.

    Article  CAS  PubMed  Google Scholar 

  33. Nishioji K, Mochizuki N, Kobayashi M, et al. The impact of PNPLA3 rs738409 genetic polymorphism and weight gain ≥10 kg after age 20 on non-alcoholic fatty liver disease in non-obese Japanese individuals. PLoS One. 2015;10(10):e0140427. doi:10.1371/journal.pone.0140427.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest. Hepatology. 2007;46(1):32–6.

    Article  CAS  PubMed  Google Scholar 

  35. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive sys-tem that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.

    Article  CAS  PubMed  Google Scholar 

  36. Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwandet-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–7.

    Article  CAS  PubMed  Google Scholar 

  37. Dawber TR, Kannel WB, Revotskie N, et al. Some factors associated with the development of coronary heart disease: six years’ follow-up experience in the Framingham study. Am J Public Health Nations Health. 1959;49:1349–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nishimura K, Okamura T, Watanabe M, et al. Predicting coronary heart disease using risk factor categories for a Japanese Urban population, and comparison with the Framingham risk score: the Suita study. J Atheroscler Thromb. 2016;23(9):1138–9.

    Article  PubMed  Google Scholar 

  39. Nishioji K, Sumida Y, Kamaguchi M, et al. Prevalence of and risk factors for non-alcoholic fatty liver disease in a non-obese Japanese population, 2011–2012. J Gastroenterol. 2015;50:95–108.

    Article  CAS  PubMed  Google Scholar 

  40. Kojima S, Watanabe N, Numata M, et al. Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol. 2003;38:954–61.

    Article  PubMed  Google Scholar 

  41. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53(6):1874–82.

    Article  PubMed  Google Scholar 

  42. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver diseases: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.

    Article  CAS  PubMed  Google Scholar 

  43. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  PubMed  Google Scholar 

  44. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.

    Article  CAS  PubMed  Google Scholar 

  45. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholicfatty liver disease. Nat Genet. 2008;40:1461–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Palmer ND, Musani SK, Yerges-Armstrong LM, et al. Characterization of European ancestry nonalcoholic fatty liver disease associated variants in individuals of African and Hispanic descent. Hepatology. 2013;58:966–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hernaez R, McLean J, Lazo M, et al. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol. 2013;11:1183–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang Y, Cai W, Song J, et al. Association between the PNPLA3 I148M polymorphism and non-alcoholic fatty liver disease in the Uygur and Han ethnic groups of northwestern China. PLoS One. 2014;9:e108381.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lee SS, Byoun YS, Jeong SH, et al. Role of the PNPLA3 I148M polymorphism in nonalcoholic fatty liver disease and fibrosis in Korea. Dig Dis Sci. 2014;59:2967–74.

    Article  CAS  PubMed  Google Scholar 

  50. Cresci S, Wu J, Province MA, BARI 2D Study Group, et al. Peroxisome proliferator-activated receptor pathway gene polymorphism associated with extent of coronary artery disease in patients with type 2 diabetes in the bypass angioplasty revascularization investigation 2 diabetes trial. Circulation. 2011;124(13):1426–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Keiji Shimada, Yoshio Sumida for analyzing histological findings, and Keiko Yamamoto and Nozomi Tochiki for technical support.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan

    Yuya Seko, Kanji Yamaguchi, Naoki Mizuno, Keiichiro Okuda, Masashi Takemura, Hiroyoshi Taketani, Tasuku Hara, Atsushi Umemura, Taichiro Nishikawa, Michihisa Moriguchi, Kohichiroh Yasui & Yoshito Itoh

  2. Health Care Division, Kyoto Second Red Cross Hospital, Kyoto, Kyoto, Japan

    Mai Kamaguchi, Kenichi Nishioji, Naomi Mochizuki & Masao Kobayashi

  3. Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan

    Kojiroh Mori & Saiyu Tanaka

  4. Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Kentaro Matsuura & Yasuhito Tanaka

Authors
  1. Yuya Seko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kanji Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoki Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keiichiro Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masashi Takemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroyoshi Taketani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tasuku Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Atsushi Umemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Taichiro Nishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michihisa Moriguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kohichiroh Yasui
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mai Kamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kenichi Nishioji
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Naomi Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Masao Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kojiroh Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Saiyu Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kentaro Matsuura
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yasuhito Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yoshito Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshito Itoh.

Ethics declarations

Conflict of interest

Dr. Yoshito Itoh received lecture fees from Bristol-Myers Squibb Company, Janssen Pharmaceutical K.K, AbbVie Inc., Merck Sharp and Dohme, Gilead Sciences Inc., and received a research grant from Bristol-Myers Squibb Company, AbbVie Inc., Merck Sharp and Dohme, Otsuka Pharmaceutical Co., Ltd. Dr. Yasuhito Tanaka received lecture fees from Bristol-Myers Squibb Company, Janssen Pharmaceutical K.K, Merck Sharp and Dohme, Gilead Sciences Inc., Chugai Pharmaceutical Co., Ltd, and received a research grant from Bristol-Myers Squibb Company, AbbVie Inc., Chugai Pharmaceutical Co., Ltd.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 48 kb)

Supplementary material 2 (DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seko, Y., Yamaguchi, K., Mizuno, N. et al. Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease. J Gastroenterol 53, 438–448 (2018). https://doi.org/10.1007/s00535-017-1372-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-017-1372-8

Keywords

Search

Navigation